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Over 300 million people worldwide live with a rare disease, yet roughly 95% of these conditions lack an FDA-approved treatment. Traditional clinical trials face significant challenges in this segment. Barriers include small patient populations with correspondingly limited statistical power. Yet emerging biosimulation and virtual trial methods offer a promising path forward., says Oxana Iliach, vice-chair of the regulatory scientific committee of the International Rare Diseases Research Consortium and senior director of regulatory strategy and Policy at Certara.
In the following Q&A, Iliach and Rajesh Krishna, Ph.D., distinguished scientist, drug development solutions at Certara, explained jointly over email
With many rare diseases still lacking an approved treatment, how can biosimulation and virtual trials specifically overcome the statistical challenges of small patient populations?
Iliach and Krishna: Biosimulation and virtual trials can significantly improve the statistical precision around delta of effect when studying small patient populations in the context of rare diseases. Here’s how they can help:
- Ability of biosimulation allows researchers to extrapolate results from a smaller cohort by simulating a broader range of patient responses. This provides a more robust understanding of the disease and treatment effects, even in small populations.
- Virtual trials use patient-specific data, such as genetic information, biomarkers, and clinical histories, to simulate how individuals may respond to a particular treatment. Through these virtual trials, one can create virtual cohorts of patients with a rare disease. These cohorts can then be simulated to mirror various patient subgroups, thus overcoming the difficulty of recruiting enough patients. It allows for testing of drug efficacy across a range of variables without needing to physically enroll large numbers of people.
- One of the challenges in small patient populations is the lack of sufficient control groups for comparison in clinical trials. In rare diseases, where finding a control group can be nearly impossible, biosimulation can generate synthetic control arms using model-based meta-analytical outputs. These synthetic arms are constructed using data from real patients (from registries or past studies) or simulated data, providing a comparison for the experimental treatment.
- Adaptive trial designs can be powered by biosimulation to simulate different clinical trial scenarios and help researchers identify the most efficient and cost-effective trial protocols. This reduces the need for large patient numbers and ensures that small populations are still adequately represented in the trial’s statistical analysis. These simulations can also predict how the disease progresses and how patients will respond to treatment, optimizing dosing schedules and endpoints for the rare disease. Disease progression modeling can then be used to determine change in treatment induced effect on long term durability.
- Biosimulation helps improve statistical power in studies of rare diseases by simulating larger populations based on a limited number of real-world patients. This allows for more precise conclusions to be drawn from fewer patients, increasing the likelihood that a statistically significant effect can be observed even with a small sample size. One can also capitalize on shared molecular etiologies to enhance the subject pool across “like” indications.
Rajesh Krishna
Can you summarize the main ways biosimulation and virtual trials can help in the rare disease space?
Iliach and Krishna: In sum, biosimulation and virtual trials enable more efficient and scientifically rigorous approaches to testing and developing treatments for rare diseases, despite the challenges posed by small patient populations. These methods help maximize the data available and simulate clinical scenarios to generate insights that are statistically robust, thus overcoming many of the traditional barriers in rare disease research.
What specific policy changes and collaborative frameworks could create more equitable development opportunities, especially for ultra-rare conditions that might not be commercially viable traditionally?
Iliach and Krishna: There are multiple ways how policies could stimulate and encourage development of drugs for rare diseases, specifically for ultra-rare conditions that might not be commercially viable traditionally. Following are a few considerations:
- Provide incentives for development by allowing flexibility in application of current regulatory requirements and engagement opportunities with health authorities to facilitate development and additional exclusivity for non-commercial products.
- Increase international regulatory collaboration by encouraging incorporation of reliance procedures into current polices.
- Increase international sponsor engagement by encouraging drug developers to work collaboratively with researchers, patients, healthcare providers, and other key stakeholders.
- Create “sand boxes” for access policies and health technology assessments, with understanding that there would be very limited clinical data available to support pricing decisions.
How might the increasing role of patient advocacy organizations in regulatory decision-making fundamentally reshape traditional clinical trial design?
Oxana Iliach
Iliach and Krishna: The reality is that every one of us sooner or later will become a patient. As such, the fundamental shift should start within the pharmaceutical industry by trying to step into the “patients’ shoes” by engaging with the patient organization at the earliest stages of product development. It is also well known that the desperation to have a treatment may drive a patient to literally try anything and as such reduce requirements for product safety and efficacy. To ensure the balance between patient-driven priorities and scientific rigor in the rare disease space, the collaborative approach is required between regulators, patients’ organizations, and industry. It is well known that some rare diseases receive more attention than others; for example, rare oncology and neurological disorders. One of the options to address these disparities in rare disease drug development is to create a consortium between overarching patients’ organizations such as NORD and EURORDIS together with health authorities and industry associations to establish a framework and developing a working group based on the therapeutic areas to develop joint scientific and regulatory approach with the focus on patient needs. These working groups could work cooperatively on developing a clinical master protocol and/or generating case studies to help facilitate and accelerate drug development for rare diseases.
Filed Under: clinical trials, Drug Discovery
